PT85775B - METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS OR OF CAFETERIA PRODUCTS CONTAINING TREATED LIPID REGULATORS - Google Patents

Abstract

Cholestyramine can be administered orally either alone or in combination with one or more other beneficial agent(s) in compositions in which the cholestyramine has been suitably pretreated.

Description

Background

Cholestyramine is a well-known ion exchange resin that has pharmaceutical utility as an antihyperlipemic agent that lowers cholesterol. During normal digestion, many of the bile acids secreted in the duodenum are recaptured at specific receptor sites in the ileum and return to the liver through enteropathic circulation. Cholestyramine resin combines with bile acids to form an insoluble complex that is secreted in faeces, thereby helping, eventually, to lower cholesterol levels.

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Although cholestyramine is highly effective, its grainy or sandy texture makes it unpleasant in appearance and in the mouth. A result of this unpleasant aspect is to reduce tolerance in individuals who regularly ingest the resin who can avoid taking all the resin they need.

Combination products, i.e. compositions containing cholestyramine and one or more useful substances or drugs, are difficult to formulate due to the ionic character of the resin. For example, an acidic drug cannot be administered easily, together with cholestyramine because the drug can bind ionic positions in the resin, and thus reduce the effectiveness of the two agents.

The Invention

It has been found that suitable compositions containing cholestyramine or other ionic lipid modifiers can be produced by pretreating the ionic lipid modifier using a given regimen. Optionally, the treated lipid modifier (s) can be combined with at least one other useful substance, for example, a second lipid reducing agent. In one embodiment, the cholestyramine resin granulates to yield granules whose particle size ranges from about 10 to about 100 microns. These granules are then coated with a material that is resistant to acids, but soluble in the intestinal juice of the duodenum or other portions of the intestine where the bile acids are secreted. This pretreated cholestyramine can then be administered alone or in combination with other useful drugs or substances.

Benefits

The compositions of the invention have several advantages over known compositions containing cholestyramine resin. The pretreated cholestyramine resin is in a form that makes it easily included in various dosage forms such as candy bars, chewing gums, liquid suspensions. liquid and semi-solid, sprinkler systems, tablets, caps and the like.

In addition, the coating process used in the pre-treatment virtually ensures that cholestyramine or another ionic component does not react to a significant extent before reaching the exact location in the gastro-intestinal tract so that its effectiveness is maximized.

These and other aspects and advantages of the invention will be readily apparent upon consideration of the following description of the invention.

Description of the Invention

The invention involves a composition and method by which the interaction between cholestyramine and other drugs, especially other lipid-regulating drugs, is minimized, when cholestyramine is ingested alone or in combination by human individuals.

The compositions of the invention contain:

(a) at least one lipid regulator that has been pre-treated to make it stable until it reaches the close section or other appropriate areas of the intestine, and, optionally, (b) at least one other therapeutically active substance.

The process of the invention involves the oral administration of a drug or a combination of drugs to a patient in need of hyperlipidemic therapy. As a general rule, the process involves the use of a composition or series 3e compositions that are formulated in such a way that the active or reactive agents in each drug are absorbed into the body with maximum efficiency.

It is preferable that cholestyramine or another ionic lipid regulator is pre-treated through a process that involves:

(1) granulation; and (2) coating with an acid-resistant coating material.

It is highly preferred that the coating material used in step (2) is soluble in its su • mnwnKaxr, ♦ li

of a proximal duodenal region of the intestine, that is, in the portion of the intestine in which bile acids are present in significant amounts. By significant amounts ”applicants mean amounts in which bile acids can effectively bind to the reactive positions of an ionic lipid modifier such as cholestyramine so that their concentration in the blood stream drops.

Lipid regulators

The drug combinations of the invention combine a lipid regulator, for example, cholestyramine and at least one other beneficial or therapeutic material.

The lipid regulators suitable in this invention can be chosen from any of the conventionally used ones whose ionic character makes them suitable for the binding of bile salts and / or other fatty materials. Suitable lipid regulators include those that act by ionic mechanisms to remove one or more fatty substances from the blood stream and increase their concentration in faecal excretions.

Preferred lipid modifiers of the ionic type are cholestyramine, cholestipol, and equivalents and their pharmaceutically acceptable salts, for example colestipol HCl. Combinations of oolestyramine and other anion exchange resins are contemplated. Combinations containing lipid modifiers that do not act by ionic mechanisms are also contemplated, for example, genfibrozil and cholestyramine can be combined.

Cholestyramine is a pharmacologically important anion exchange resin. The exchange functions of basic quaternary ammonium in xaesine are linked to a styrene-di-vinylbenzene copolymer backbone.

Its structure is;

• ll

where n is a function of molecular weight.

Cholestyramine has been shown in animals and clinically in man to increase the fecal excretion of endogenous bile salts, thereby significantly decreasing the absorption of fats and fatty materials. This resin also has the ability to lower plasma cholesterol levels by binding bile salt anions in the small intestine. An article that discusses the binding capacity of resins is W. J. Johns and T. R. Bates, Quantification of the Binding Tendencies of Cholestyramine I, Effect of Structure and Added Electrolytes on the Binding of Unconjugated and Conjugated Bile-Sal Anions ”Journal of Phar. Science, vol. 58, n2. 2, February, 1969, pages 179-83. The content of this article is therefore incorporated by reference.

Applicants contemplate formulations in which cholestyramine and / or other ionic lipid modifiers are used in combination with one or more agents that inhibit cholesterol production and / or absorption. Suitable agents include, but are not limited to, fibric acid derivatives, coloreductose inhibitors, anti-hyper lipoproteinemics and the like.

Suitable lipid lowering / regulating agents include - but are not limited to - genfibrozil, dextrothyroxine, and fibrates, for example, fenofibrate, clofibrate, bezafibrate, ciprofibrate, mevinolira, synvinoline, niacin, hormonal preparations, for example, agents containing T3 - and / or T4-, fish oils and / or extracts of such oils, eptastine, neomycins, probucol, nicotinic acid, and equivalents, as well as their pharmaceutically acceptable salts and esters. for example, sodium dextrothyroxine, genfibrozil Hcl and

equivalent. Genfibrozil and its pharmaceutically acceptable derivatives are preferred.

genfibrozil and its analogs are discussed in U.S. Patents 5,674,836 and 4,126,637, their descriptions are incorporated herein by reference.

Mixtures of lipid moderators that are not ionic in character are functional when they are mixtures that contain a plurality of ionic type moderators and a plurality of one or more other types.

The amounts in which the lipid reducing agents are present in the final therapeutic compositions vary according to the nature of the agent (s) chosen and the therapeutic effect that is to be achieved.

As a general rule, in compositions containing cholestyramine, the concentration of cholestyramine will vary from about 5 to about 80, preferably from about 30 to about 60 weight percent, based on the weight of the total composition.

Unless otherwise stated, all percentages set forth herein are weight percentages based on the weight of the total composition.

If a second lipid is used - that is, one that is not ionic in character - it is usually present in a concentration of about 5 to about 80, preferably about 30 to about 60, weight percentage by weight.

In addition to cholestyramine and / or other lipid-lowering agent (s), the compositions of the invention may also contain a wide variety of other beneficial drugs or substances.

The categories of suitable drugs that can be used in combination with the present moderators) of treated lipids can vary widely and, as a general rule, represent any stable combination of drugs. Illustrative categories and specific examples include:

a) Anti-coughs, such as dextrometrophane, dextromethorphan hydrobromide, noscapine, carbetapentane citrate and clofedianol hydrochloride:

b) Antihistamines, such as chloropheniramine, maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate;

c) Decongestants, such as phenylprine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, ephedrine hydrochloride;

d) Various alkaloids, such as codeine phosphate, codeine sulfate, and morphine; and

e) Mineral and vitamin supplements such as potassium chloride and calcium carbonates.

These materials can be used alone or in combination within the ranges specified above

The weight percentage of non-lipid-modifying drugs or the corresponding salts, based on the weight of the total composition, will vary from about 2% to about 80% and, preferably, from about 5% to about 50% by weight , which amounts may vary according to the permitted therapeutic dosage.

The drugs, minerals and vitamins discussed above can be used in any of their pharmaceutically acceptable forms. Thus, salts, for example, hydrochlorides, borates, pamoates, and the like, as well as other analogs, metabolites and / or pro-drugs related thereto, can be used. The mixtures are usable.

A preferred group of materials to combine with the lipid modifiers treated in the invention in orally administrable compositions include phenylbutazone, warfarin, and chlorothiazide, as well as tetracycline, penicillin G, phenobarbitol, thyroid and thyroxine preparations, chloropropamide digitalis niacin-6 ^ C, ascorbic acid, aspirin, salicylic acid, phenobarbitol ^ C, sulfodiazine, linocomycin Hcl, tetracycline Hcl and equivalents to their pharmaceutically acceptable analogues, for example, salts. Combinations of these drugs can be used.

Pre-Treatment Technique process, by which the reduction is

primary ionic lipid tor in order to maximize its compatibility with other drugs in the system is a new process.

granulation step involves agglomeration or other suitable procedure to produce granules or other particles, generally spherical whose size varies from about 30 to about 100 microns. Apparatus suitable for the granulation step is well known in the art. If the lipid modifier is provided in a form that is suitable for coating, the granulation step can be omitted, i.e., granulation is optional.

Following granulation, the particles are then coated with a pharmaceutically acceptable material that is resistant to acids, so that the granules remain coated when they pass through the stomach after ingestion. Such materials are, as a general rule, so-called enteric coating materials and are well known in the art. Mixtures of such materials can be used.

It is highly preferable that the acid-resistant coating is also soluble in the region of the intestine in which the bile salts and other fatty substances can be absorbed, or bonded by the resin, so that they leave the blood stream and are shipped with the material fecal. Suitable coating materials are commercially available materials, or combinations of some, that have the necessary solubility.

As a general rule, the coating material should be insoluble at the pH generally found in the stomach, but soluble at the pH generally found in the proximal intestine. As a general rule, the coating material should be insoluble at pH (s) below 5, preferably at pH (s) below 4, but soluble at pH, from the proximal intestine, ie about 4 to about 7, preferably, about 4 to about 5.

Preferred coating materials are polymers or polymer precursors (for example monomers and / or intermediate resins) whose films have the solubility properties discussed above. The mixtures are usable.

method by which the coating material (s) is applied to the primary lipid regulator is not crucial.

coating material. - -. / _

It is sufficient for the purposes of this invention that this lipid regulator is coated, encapsulated or otherwise treated so that a small or no association of the ionic lipid regulator takes place in an acidic environment, i.e. in the stoma.

Optionally, one or more of the other drugs used in the combinations of the invention can be suitably pretreated. the system (W-L PD «

A preferential treatment involves covering up the flavor established in U.S. SN. 811.601 3456-7-DAS).

Dosage Forms

The final dosage forms in which the drug combinations of the invention come in can vary widely. If the compositions are for oral administration, it is considered that any system that provides ingestion via the gastro-intestinal tract can be used. Formulations for ingestible tablets, granules, sprays, suspensions, gels, candy bars, chewing gum, chewing gum, lozenges, and the like are considered. Combinations of these, for example, lozenges with chewing candy centers are suitable.

Two preferred dosage forms are formulations of edible bonbons and nascar gum formulations. Such formulations may contain fillers, waxes, sweeteners, stabilizers, flavoring agents, fragrance enhancers, processing aids, and the like, which are conventionally used in confectionery techniques. For example, suitable sweeteners include aspartan, saccharin, glucose, sucrose, fructose, xylitol, and equivalents and combinations thereof.

Excipients, such as fillers, stabilizers and other additives conventionally used in the pharmaceutical industry and in the candy and confectionery industry, can be used in suitable amounts in the compositions of the invention.

The dosage forms produced in accordance with the invention are used to deliver drugs to human receptors in amounts suitable for the desired therapeutic effect (s), that is, dosage levels that are consistent with the patient's therapeutic needs and desires. your doctor. Thus, the daily dosage levels for the lipid regulators used in the invention are well known and need not be presented here. Characteristically, sources of reverence such as the Physicians * Desk Reference, and the drug manufacturing specifications and instructions can be consulted to determine the appropriate drug concentration levels and / or dosing regimens for the inventive combinations.

Examples

The following examples illustrate the invention:

Example I

This example shows the effect of pH on the binding of genfibrozil to untreated cholestyramine.

Solutions of genfibrozil were prepared in 0.05 M acetate buffer, pH 4.5, and in 0.05 M phosphate buffer pH 6.0 and 7.5 as follows:

Genfibrozil solutions were prepared by adding an excess of genfibrozil to the desired volume of buffer and stirred overnight on a shaker at room temperature. The resulting suspension was filtered in vacuo. The concentration of genfibrozil was determined by absorbance at 280 nm, using

65.6

Ultraviolet absorbance measurements were obtained on a Beckman DU-7 spectrophotometer.

The measurements of optical rotation in line D of sodium were obtained with a Rudolph Auto-Pol 2.

All experiments were carried out (unless otherwise stated) in 50 or 15 ml polypropylene centrifugal tubes with a cap. Missions have always been agitated

at 75 RPM in a Vanderkamp continuous-release apparatus heated to 37 ° C Sodium glycocholate: Sigma; Lot # 75f-5O83 Cholestyramine: Rohm & Haas, Amberlite - IRP 276, Lot # 6x686.

The concentration of genfibrozil in ca * · 'of the buffer, determined by absorbance at 280 nm was: pH 4.5, 0.014 mg / ml; pH 6.0, 0.150 mg / ml; pH 7 * 5 w 1.711 mg / ml. Cholestyramine (10 mg) was added to 20 ml of each solution of genfibrozil and the mixtures were stirred for 2 hours. The mixtures were filtered and the concentration of unbound genfibrozil was determined.

The solubility of genfibrozil at pH

4,5 is very low, as shown in Table I. Thus, although genfibrozil has a high affinity for cholestyramine, only a very small amount of genfibrozil is available to bind to this pH. at pH 6.0 parallel to the increase in the solubility of genfibrozil (Table I) there is an increase in the amount that binds. At pH 7.5, the amount of genfibrozil in the solution. tion is less than the amount needed to saturate the resin, and, in fact, saturation occurs. It matters that the pH (s) of

4.5 and 6.0, the resin does not bind 100% of the available genfibrozil even if unused positions are present.

TABLE I:

cholestyramine that of

various pH (§). mmol Genfibrozil pH On / g Resin 4.5 0.11 6.0 0.60 7.5 2.83

Example II

This example shows the effect of pH on the binding of genfibrozil that was treated according to the invention. The experimental procedure was the same as in Example I. The coated material contains fifty percent active resin.

Table II: Binding of Genfibrozil to Treated Cholestyramine mmol Genfibrozil

22 On / g Resin 4.5 0.06 6.0 0.66 7.5 2.85

Reasonable variations, such as those that would occur to those skilled in the art, can be made here without departing from the scope of the invention.

Claims (1)

Process for the preparation of a pharmaceutical composition characterized by being incorporated as an active ingredient in a concentration of about 5% to 80%, preferably 50% to 60% by weight, based on the total composition weight, at least one regulator of lipids that have been pre-treated to make it stable until it reaches the proximal section of the intestines. 2. A process according to claim 1, characterized in that the lipid regulator is ionic in character. - 5§ » The process according to claim and additionally incorporated in the compc) is a lipid regulator. tion 2, characterized by the presence of a drug -4a _ Process according to claim 3, characterized in that the lipid regulator is cholestyramine. -5â - Process for the preparation of a candy characterized by incorporating a composition according to claims 1, 3 or 4. -6â - Process for the preparation of a chewing gum, characterized in that a composition according to claims 1, 3 or 4 is incorporated. The applicant declares that the first application for this patent was filed in the United States of America on September 26, 1986, under Serial number 912,902. Lisbon, September 23, 1987